Effects of cyclosporine A and prednisone treatment on mixed meal disposition in dogs with hepatic denervation

BACKGROUND: Compared with untreated dogs, normal dogs treated for 7 days with cyclosporine A and prednisone exhibited a 25% reduction in the absorption of glucose from a mixed meal and a 4- to 5-fold increase in net hepatic glucose uptake, without reduction of postprandial glycemia. The hepatic nerves are also involved in directing postprandial glucose disposition. Therefore, we hypothesized that the combination of immunosuppressive therapy and hepatic denervation would create additional alterations in the disposition of glucose from a mixed meal. METHODS: Six 24-hour-fasted conscious dogs that had undergone surgical hepatic denervation (DN) and received cyclosporine A 15 mg/kg daily and prednisone 5 mg twice daily for 7 consecutive days before study (DN + CyP group) received an intragastric mixed-meal feeding over 30 minutes. The results were compared with those from a group of 8 normally innervated dogs receiving the same immunosuppressives (CyP group). RESULTS: Arterial blood glucose concentrations remained elevated over basal in both groups at the end of the 480 minutes postprandial period. The arterial plasma insulin response was no different in the 2 groups (area under the curve 119+/-25 and 100+/-40 nmol/L in DN + CyP and CyP, respectively). In both groups, net gut glucose output was equivalent to approximately 45% of the glucose in the meal, and net hepatic glucose uptake accounted for approximately 54% to 66% of the absorbed glucose. Arterial blood lactate concentrations and net hepatic lactate output were not different between groups at any time. CONCLUSIONS: Immunosuppressive therapy is responsible for most of the alterations in postprandial carbohydrate metabolism observed in this model; the lack of hepatic nerves has little additional impact.

Dogs with chronic hepatic denervation and 7 days of treatment with cyclosporine A and prednisone exhibited prolonged hyperglycemia and enhanced net hepatic glucose uptake in response to a mixed meal. These effects are apparently due to immunosuppressant therapy and not to the hepatic denervation. Individuals receiving immunosuppressive therapy are at risk for alterations in glucose disposition in response to mixed meal ingestion.